Inhaler

ABSTRACT

An inhaler has a housing containing a chamber ( 1   a ) providing a reservoir ( 8 ) for liquid providing an active ingredient to be supplied to a liquid outlet ( 10   a ). First and second electrodes are spaced apart ( 11  and  12 ) with the first electrode being spaced apart ( 11  and  12 ) with the first electrode being provided at or adjacent the liquid outlet ( 10   a ). A voltage supply ( 5, 7 ) is activated in response to air flowing through an air inlet ( 30 ) of the housing to provide a potential difference between the first and second electrodes ( 11  and  12 ) to create an electric field for causing comminution of liquid issuing from the liquid supply outlet ( 10   a ) to produce a stream of electrically charged comminuted matter for supply to the nasal passages of a user via an outlet ( 4 ) of the housing.

This invention relates to an inhaler for enabling delivery of an activeingredient to the nasal passages.

Conventionally, nasal inhalers are used for the supply of decongestantssuch as oxymetazoline and the like. The nasal passages are also a goodway of supplying drugs and other medicaments into the bloodstream fortreatment of ailments which are not specific to the nasal passages.

Conventional hydraulic/pump action nasal inhalers fire or eject largedroplets of liquid into the nose. These droplets are polydispersed, thatis they have a broad spectrum of sizes. The deposition of such dropletsis primarily due to their own inertia which can lead to a very patchydistribution of the liquid. Indeed excessive deposition in one regioncan lead to the droplets coalescing and flowing out of a nostril or downthe back of the throat which can cause an unpleasant taste or, worse,lead to detrimental side effects as a result of the drug being deliveredto the digestive or pulmonary system.

It is an aim of the present invention to provide a device which enablessatisfactory and efficient supply of a substance such as a medicament orother active ingredient to the nasal mucosa avoiding deposition innon-target regions such as the lungs or the stomach.

A process for producing comminuted matter known as electrohydrodynamiccomminution is described in detail in, for example, GB-A-1569707. Inthis process, a dispersed spray or cloud of comminuted matter such asliquid droplets which are all of substantially the same size(monodispersed) is produced by subjecting liquid emerging from an outletto an electric field.

The device described in GB-A-1569707 is large, produces highly chargeddroplets and is intended primarily for spraying of crops.

Inhalers have been proposed that exploit electrohydrodynamic comminutionbecause they have the advantage, unlike conventional inhalers, ofproducing a monodispersed (substantially all the same size) mist orcloud of droplets so that the droplets may be targeted more accurately.However, because the conventional wisdom is that it is difficult, if notimpossible, to spray electrically charged material into a cavity,previous attempts at producing inhalers using electrohydrodynamictechniques require that the comminuted matter be electrically dischargedbefore inhalation. For example, EP-A-0234842 teaches that it isnecessary to discharge the resulting comminution before inhalation toprevent it being deposited only on the wet conductive surfacesimmediately inside the mouth or throat.

The present inventors have, surprisingly, found that, by a combinationof electrohydrodynamic, discharging or partial discharging techniquesand aerodynamic forces on the resultant comminution, an inhaler can beprovided which generates by electrohydrodynamic means electricallycharged comminuted matter which can be inhaled so as to deposit evenlyonto the conductive inner surface of the nasal passages from whence anactive ingredient carried by the comminution can be rapidly absorbedinto the bloodstream without being inhaled into the pulmonary system.

In one aspect, the present invention provides an inhaler havingelectrohydrodynamic comminution means arranged to be activated byinhalation by a user, which facilitates entrainment of electricallycharged comminuted matter into the air flow and thence into the nasalpassages of the user.

In one aspect the present invention provides an inhaler havingelectrohydrodynamic comminution means with the electrode or electrodesof the comminution means being shielded from the user so that the usercannot make direct electrical contact with the electrodes.

In one aspect the present invention provides an inhaler wherein thematerial to be inhaled is electrohydrodynamically produced and theelectrical charge and/or size of the comminuted material, generallydroplets, are/is controlled so that the material can be deposited evenlyinto the nasal passages but supply to the pulmonary system or the backof the throat is prevented, thereby enabling the inhaler to be used forthe supply to the nasal passages of medicaments which may produceunpleasant or undesirable effects if they were supplied to the pulmonaryor digestive system.

In one aspect the present invention provides an inhaler having a supplyof liquid carrying an active ingredient, means for supplying the liquidto an outlet and means for subjecting liquid issuing from the outlet toan electrical field sufficient to cause comminution of the liquid toproduce electrically charged comminuted matter for inhalation by theuser, the liquid or liquids being selected so as to control the mannerin which active ingredient in the electrically charged comminuted matteris released when the electrically charged comminuted matter is depositedin the nasal passages. The liquid may be an oil or alcohol-basedformulation allowing rapid supply of the active ingredient into thebloodstream via the surfaces of the nasal passages. As anotherpossibility, the liquid may be such that the resulting comminuted matterhas a gel-like structure enabling continued release of the activeingredient.

In one aspect the present invention provides an inhaler having means forsubjecting liquid issuing from an outlet to an electric field sufficientto cause comminution of the liquid and means for causing electricallycharged comminuted matter to be deposited onto the surfaces of the nasalpassages. The latter means may comprise means for causing orfacilitating an air flow through the inhaler which entrains the chargedcomminuted matter such an air flow may be generated by inhalation by auser, by artificial means such as a pump or a combination of both ofthese.

In one aspect, the present invention provides an inhaler havingcomminution means arranged to provide an electric field which has astrength which reduces rapidly in the direction of liquid flow fromliquid supply means enabling liquid comminuted by the electric field tobe easily entrained in an air flow path from the inhaler into a nostrilof a user during use.

In one aspect, the present invention provides an inhaler having meansfor supplying liquid to an outlet and means for subjecting liquidissuing from the outlet to an electrical field sufficient to causecomminution of liquid issuing from the outlet, and means for generatingan electrical potential at the one of the first and second electrodesmost remote from the liquid outlet, said means for generating theelectrical potential comprising means for generating an ion current forindirectly charging said one electrode.

In this aspect, the ion current generating means may comprise a furtherelectrode located adjacent the one electrode and means for providing ahigh resistance path to earth from said one electrode. The highresistance path to earth may be provided by an actual resistor in serieswith said one electrode or, for example, a resistive or semiconductivecoating on said one electrode. Indirect charging of said one electrodereduces the possibility of deposition of comminuted matter onto said oneelectrode because any electrically charged comminuted matter whichapproaches said one electrode will be at least partially electricallydischarged by the generated ions. Furthermore, a more even deposition orgreater penetration within the nasal passages should be achieved becauseof the at least partial discharge of some of the comminuted matter bythe ion generating means.

In one aspect, the present invention provides an inhaler having meansfor supplying liquid to a comminution site and electrical currentlimiting means for limiting the supply of electrical current to thecomminution site. The current-limiting means may comprise a dielectricor semi-insulating coating or sleeve or a high resistance coupled in thepath from a high capacitance high voltage source to an electrode.Otherwise, a low capacitance high voltage source, such as apiezoelectric voltage source, may be used.

In one aspect, the present invention provides an inhaler capable ofsupplying opposite polarity comminutions to the nasal passages.

In one aspect, the present invention provides a dispensing device, whichmay be an inhaler, having means for supplying liquid to an outlet, meansfor subjecting liquid issuing from the outlet to an electrical fieldsufficient to cause comminution of liquid issuing from the outlet andmeans for controlling the size of individual elements of the comminutedmatter, for example droplets, in the resulting comminution.

Embodiments of the present invention will now be described, by way ofexample, with reference to the accompanying drawings, in which:

FIG. 1 illustrates schematically use of an inhaler in accordance withthe present invention;

FIG. 2 shows a diagrammatic, part-cross-sectional view of an embodimentof an inhaler in accordance with the present invention;

FIG. 3 shows a block schematic electrical diagram for the inhaler shownin FIG. 2;

FIG. 4 shows a part-cross-sectional view, on an enlarged scale, of partof the inhaler shown in FIG. 2 to show one example of anelectrohydrodynamic comminution site for the inhaler shown in FIG. 2;

FIG. 5 shows a part-cross-sectional view, on an enlarged scale, of partof the inhaler shown in FIG. 2 to show another example of anelectrohydrodynamic comminution site for the inhaler shown in FIG. 2;

FIG. 6 shows a part-cross-sectional view, on an enlarged scale, of partof a further embodiment of an inhaler in accordance with the presentinvention;

FIG. 7 shows a part-cross-sectional view, on an enlarged scale, of partof another embodiment of an inhaler in accordance with the presentinvention;

FIG. 8 shows very schematically another example of an inhaler embodyingthe present invention using a compressed airflow for activation;

FIGS. 9a to 9 d show droplet spectrums with FIG. 9a showing a dropletspectrum for an inhaler embodying the invention and FIGS. 9b to 9 dshowing droplet spectrums for various forms of conventional inhaler;

FIG. 10 shows a diagrammatic part cross-sectional view similar to FIG. 2of another embodiment of an inhaler in accordance with the presentinvention;

FIG. 11 shows a diagrammatic part cross-sectional view similar to FIG. 2of another embodiment of an inhaler in accordance with the presentinvention;

FIG. 12 shows, on an enlarged scale, part of the inhaler shown in FIG. 2to illustrate a modification thereof;

FIG. 13 shows very schematically a further modification of an embodimentof an inhaler in accordance with the present invention;

FIG. 14 is a diagram for illustrating the operation of an inhaler havingthe modification shown in FIG. 13;

FIG. 15 shows a part cross-sectional enlarged view of part of anotherembodiment of an inhaler in accordance with the invention; and

FIG. 16 shows a part cross-sectional enlarged view of part of anotherembodiment of an inhaler in accordance with the invention.

As illustrated schematically in FIG. 1, an inhaler 1 embodying theinvention is intended primarily for use as a pocket-sized, hand-helddevice which is actuated by a user to enable delivery of an activeingredient, drug or active ingredient into the nostril of the user. Forexample, the inhaler may be arranged to deliver a decongestant such asoxymetazoline to the nasal passages or to deliver drugs or othermedicaments such as insulin or triptans (for example Elitriptan) intothe bloodstream via the nasal mucosa. The inhaler may also be used todeliver flu vaccines such as Flumist (a product being developed byAviron of Mountain View, Calif. USA) which is arranged to be effectivein the relatively low temperature environment of the nasal mucosa.

The inhaler 1 comprises a housing 3. The housing may be made mainly ofelectrically insulative material such as a plastics material although atleast a part of the housing that a user will inevitably touch in useprovides an electrically conductive region that enables, as will bedescribed below with reference to FIGS. 2 and 3, an earth connection viathe user. The inhaler has an outlet 4 through which liquid droplets tobe inhaled are supplied to the user. The outlet 4 is sized and shaped soas to fit snugly against or slightly into the user's nostril so as tomake a reasonably air-tight seal. The outlet may be detachable from thehousing to allow different sized and shaped outlets to be used so as toenable a snug fit to different sizes of nostrils to enable, for example,use by both adults and children. Although a snug fit is desirable fromthe viewpoint of efficiency, in practice, it may be sufficient for theinhaler to be placed in close proximity to a nostril.

The inhaler 1 is rotationally symmetric about its longitudinal axis soas to be generally cylindrical. Typically, the housing will be about oneinch (25.4 mm) diameter and about 4 to 5 inches (102 to 127 mm) inlength.

FIG. 2 illustrates a part sectional view through one example of aninhaler embodying the invention, while FIG. 3 shows a block circuitdiagram of components of the inhaler.

As shown in FIG. 2, the housing 3 of the inhaler 1 has an internal wall3 a which divides the housing into first and second chambers 1 a and 1b.

In this example, the first chamber accommodates a voltage source 5 inthe form of a battery. As shown most clearly in FIG. 3, the positiveterminal of the battery 5 is connected via a user-operable switch SW1 toa reset input of a counter 6 and to a further switch SW2. Although notshown in FIG. 2, the negative terminal of the battery 5 is alsoconnected to the electrically conductive region of the housing mentionedabove so, as shown schematically in FIG. 3, the user H provides a pathto earth (ground). The switch SW1 is a conventional manually operableswitch such as, for example, a toggle or push switch. The switch SW2 isarranged to be activated by airflow and will be described in greaterdetail below. A high voltage generator 7 is coupled to the battery 5 viathe switches SW1 and SW2 and a counter 6 which is arranged to be resetby closure of the switch SW1 and which outputs the battery voltage tothe high voltage generator positive voltage input until a predeterminedcount is reached when the output of the counter goes low. The highvoltage generator may be a conventional electromagnetic high voltagemultiplier of the type supplied by Brandenburg, Astec Europe, of HighStreet, Wollaston, Stourbridge, West Midlands DY8 4PG, UK, or StartSpellman of Unit 1, Broomers Park, Broomers Hill Lane, Pulborough, WestSussex RH20 2RY, UK. As an alternative, a piezoelectric high voltagesource which has a low capacitance may be used.

The first chamber la also contains a reservoir 8 for the liquid to bedispensed by the inhaler. The reservoir may be formed as a flexiblecollapsible bag or bellows—type arrangement having a chemically inertinterior surface. Alternatively, a piston-like arrangement may be usedso that as the liquid is used up, the piston moves with the liquidsurface in the chamber so avoiding the possibility of air coming intocontact with the liquid in the reservoir. A pump 9 is provided to pumpliquid from the reservoir 8 to a liquid supply outlet pipe 10. The pipeis made of an insulating material which does not retain charge for anysignificant length of time. A suitable material is, for example,polyacetyl or Delrin (Trademark).

The liquid supply pipe 10 has an outlet nozzle 10 a. A conductive coreor rod 11 provided within the liquid outlet pipe terminates adjacent thenozzle outlet 10 a and provides a first electrode. In this example, thefirst electrode 11 is coupled to the negative or earth terminal of thebattery 5 via line 5′.

The outer surface of the insulative supply pipe 10 carries a secondelectrode 12 (see FIG. 4) extending around the pipe 10. The secondelectrode 12 is located so as to be upstream of the tip 11 a of thefirst electrode in the direction of the liquid flow through the liquidsupply pipe 10. The first electrode 11 may, as shown, be pointed.

In this example, the second electrode 12 comprises a coated electrodehaving a central conductive core 12 a which is coupled to a high voltageoutput 7 a of the high voltage generator 7 and is encased in adielectric or semi-insulating coating or sleeve 12 b. Such a coatedelectrode is described in, for example, EP-A-0186983. The coating orsleeve may have a resistivity within the range 5×10¹¹ to 5×10¹³ Ω cm anda thickness of approximately 2 mm. Suitable coatings are certain gradesof sodaglass and phenolformaldehyde/paper composites. Kite brand tubessupplied by Tufnol Limited of Birmingham, England or Paxoline may beused. The core may be formed of, for example, beads of carbon tightlypacked within the coating 12 b. The coating should have a time constantor relaxation time over which it leaks or conducts charge of, typically,approximately 10⁻⁵ seconds. The second electrode 12 may, however, beuncoated.

As can be seen from FIG. 2, the first and second electrodes 11 and 12are located well within the electrically insulative housing 4 so thatthe portion 4 a of the housing defining the chamber 1 b shields the userfrom the electrodes so that direct contact by the user with theelectrodes is avoided. The outlet 4 is sized so as to prevent a userinserting a finger into the chamber 1 b. Also, although an electricalshorting is extremely unlikely, this would occur between the first andsecond electrodes and so would not subject the user to an electricalshock.

The pump 9 is an electrically operated pump and may be, for example, apiezoelectric pump or any other suitable form of electrically ormechanically operated pump. The pump 9 is coupled to the positiveterminal of the battery 5 via the switches SW1 and SW2, and the counter6. A delay circuit 120, for example a conventional capacitor-resistor(CR) network, may be provided between the counter 6 output and the pumpso that supply of the voltage necessary to activate the pump 9 isdelayed until an electric field sufficient to cause electrohydrodynamiccomminution of liquid supplied to the nozzle 10 a has been establishedbetween the first and second electrodes.

The output of the counter 6 is also supplied, as shown in FIG. 3, to anindicator light or buzzer 13.

As shown in FIG. 2, the air flow activated switch SW2 comprises a firstelectrical contact 20 mounted on a spring biassing arm 21 secured to theinner wall of the housing chamber 1 a. The switch SW2 has an outerinsulative body 22 which is caused by the spring biassing member 21 toblock an air inlet 30 provided in the housing 3. An air path from theair inlet 30 to an aperture 32 in the partition member 3 a is defined byan insulative tubular body 33. An inner wall of the insulative tubularbody 33 carries a further electrical contact 34 coupled via conductor 35to the positive power supply terminal of the high voltage generator 7.

The air path tube 33 may be modified so as to provide air paths 33′coupling to two or more apertures 32 provided in the partition member 3a and evenly distributed about the longitudinal axis L as shown indashed lines in FIG. 2.

To use the inhaler 1, a person first inserts the outlet 4 into or placesthe outlet snugly against a nostril and then manually actuates theswitch SW1 which couples the reset terminal of the counter 6 to thepositive supply of the battery 5 and so resets the count of the counter.The user then inhales through their nose as they would if using aconventional inhaler. The air flow resulting from the user inhaling thuscauses the contact 20 of the switch SW2 to be moved towards the contact34 against the biassing force of the spring member 21. Once the contacts20 and 34 of the switch SW2 make contact, power is supplied to the highvoltage generator 7 which supplies the required high voltage, typically3 to 12 kV (kilovolts) to the second electrode 12 so as to establish thenecessary electric field between the first and second electrodes 11 and12 to provide the electrohydrodynamic comminution site. Once thiselectric field has been established, the delay circuit 120 provides thenecessary electrical power to the pump 9 which then pumps liquid fromthe reservoir to the outlet nozzle 10 a.

Liquid issuing from the outlet nozzle 10 a is electrohydrodynamicallycomminuted. The separation of the first and second electrodes 11 and 12in the radial direction (that is perpendicular to the longitudinal axisL) can be relatively small (typically about 1 cm) because the coating onthe second electrode enables the two electrodes to be close togetherwhilst suppressing any electrical breakdown of the air in between. Thisrelatively small separation results in a very high strength electricfield which drops off or reduces rapidly in the longitudinal directionL. This facilitates entrainment of the resulting charged comminutedmatter in the air flow through the tube 33 to the output 4 so reducingthe possibility of the electrically charged matter depositing on theinner wall of the chamber 1 b.

Comminuted matter then issues from the nozzle 4 and is depositeduniformly onto the conductive surface inside the nasal passages.

When a predetermined time since activation of the switch SW1 has passed,that is when the predetermined count is reached, the output from thecounter 6 goes low switching off the high voltage generator 7, the pumpand the light or buzzer 13. After use, the user then can disable thedevice by pressing the switch SW1 again to disconnect the voltage source5.

The counter 6 thus enables the user to be advised when the required doseof medicament has been delivered.

The coating or sleeving of the electrode 12 provides a current limitingeffect to prevent excessive or dangerous currents from passing betweenit and the first electrode 11.

FIG. 5 shows a modification in which the insulative liquid supply pipeand conductive core 10 and 11 of FIG. 2 are replaced by a hollowelectrically conductive capillary tube pipe 14 which provides both thefirst electrode and the outlet 14 a. In this case, the second electrode12 is a discrete uncoated electrode provided on the inner wall of thefirst chamber so as to be disposed downstream of the end of the firstelectrode 14 in the direction of liquid flow through the conductive pipe14. As shown in FIG. 5, the inhaler has an air supply pipe outlet 33″(which may be an extension of the pipe 33′ shown in dashed lines in FIG.2) which causes, in use, an air curtain to be provided in front of theelectrode to inhibit deposition of droplets on the electrode 12. Thismodification may also be made in the arrangement shown in FIG. 2.Although shown as a discrete uncoated electrode, the second electrode 12may in this case comprise an annular slot electrode or a number ofindividual electrodes distributed around the inner periphery of the wallof the second chamber 1 b. Also, the electrode 12 may be coated asdescribed with reference to FIG. 4 and may be positioned slightlyupstream or adjacent the first electrode. In this case, when anelectrical field sufficient to cause electrohydrodynamic comminution isestablished between the first and second electrodes 14 a and 12,multiple jets or cones will generally be formed at the end of theconductive pipe 14.

In use, satellite droplets are sometimes produced during theelectrohydrodynamic comminution. These satellite droplets will notgenerally present a problem and will normally deposit onto the interiorsurface of the inhaler or the second or counter electrode. However, ifthe inhalers described above are used frequently over an extended periodof time, the build-up of droplets and/or residue resulting fromsubsequent evaporation of the droplets may adversely affect theoperation of the counter electrode 12 so reducing the overall efficiencyof the device. One way to avoid this problem is to design the inhalerbody so that, for example, the portion 4 a of the housing defining thechamber 1 b can be removed (for example the housing portion 4 a may beconnected by screw-thread connected to the housing portion 4 b) toenable a user to wipe the counter electrode to remove deposited dropletsor other matter. An alternative, automatic means of maintaining theoperational function of electrode 12 is described below.

FIG. 6 shows a part-cross-sectional view of mainly the lower chamber 16of another inhaler embodying the invention. The internal construction ofthe upper chamber 1 a is essentially the same as that described abovewith reference to FIG. 2.

In FIG. 6, the counter electrode 12′ is mounted to the inner wall 1 b ofthe lower chamber 1 b. The counter electrode 12′ may be annular or maybe formed by a discrete single point electrode or a number of separateelectrically connected electrodes spaced apart around the wall 1 b′.

The counter electrode 12′ is, in this example, an uncoated electricallyconductive electrode which is coupled via wire 50′ and a resistor R tothe conductor 5′ which is coupled to the negative or earth terminal ofthe voltage source 5.

A further electrode 120 is mounted in a conventional manner (not shown)in the lower housing 1 b so as to be considerably closer to the counteror second electrode 12 than to the first electrode 11. Typically, forthe dimensions given above for the inhaler, the electrode 120 may be 2mm from the counter electrode 12′ and 5 mm from the first electrode 11.The counter electrode 120 is coupled via the conductor 7 a to the highvoltage output of the high voltage generator 7 (not shown in FIG. 6).

When an inhaler having the structure shown in FIG. 6 is used, the highvoltage applied to the electrode 120 causes ions to be generated bycorona discharge from the electrode 120. These ions migrate to theclosest conductive body—in this case the counter electrode 12′—soproviding an ion current to earth via the counter electrode 12′ and theresistor R which may, typically, have a value of 600 megaohms. Thisenables the counter electrode 12′ to be indirectly charged to therequired electrical potential. Any charged comminuted matter issuingfrom the nozzle 10 a which is inadvertently attracted toward the counterelectrode 12′ will be at least partially electrically discharged by theion current generated by the ion generating electrode 120 so reducingthe likelihood of the charged matter depositing onto the counterelectrode 12′ and obviating the need for a user to wipe the counterelectrode periodically.

FIG. 7 illustrates a modification of the arrangement shown in FIG. 6 inwhich the resistance provided by the coating of the counter electrode12″ is sufficient to enable the required electrical potential to beachieved at the counter electrode 12″ without the need for the resistorR. In other respects, the arrangement shown in FIG. 7 operates in thesame manner as the arrangement shown in FIG. 6.

Although FIGS. 6 and 7 show only one ion generating electrode 120, aplurality of ion generating electrodes 120 may be provided around theliquid supply pipe. As another possibility, the ion generating electrodemay be provided by a knife edge or wire surrounding the liquid supplypipe.

It has been found that the arrangements shown in FIGS. 6 and 7 enable amore even distribution of comminuted matter to a greater depth withinthe nasal passages; thus improving the uniformity of dropletdistribution still further. This is believed to arise becauseelectrically charged comminuted matter which comes into the vicinity ofthe ion injecting electrode 120 will have been at least partiallyelectrically discharged so that some of the comminuted matter which isinhaled will be less highly charged and will therefore have a tendencyto be deposited further into the nasal passages.

The air flow path in FIGS. 6 and 7 may be modified as described abovewith reference to FIG. 5 to provide the second electrode with aprotective air curtain.

In the arrangements described above, the airflow switch SW2 is activatedby the user inhaling. It is, however, possible that the user may be sofrail that they are not capable of inhaling sufficiently strongly toactivate the switch SW2. In such a case, the inhaler may be provided, asshown in FIG. 8, with an adaptor 100 which couples around the area ofthe switch SW2 and can be connected via a pipe 101 to a manuallyactuable device 102 such as a bladder or bellows which can be squeezedby the patient or another person such as a doctor, nurse or carer toforce a flow of air to open the air inlet 30 and close the switch SW2 orto a pressurised air or gas bottle or a compressor which may beelectrically operated to supply air at the desired flow rate down thepipe to the air inlet 30.

FIGS. 9a to 9 d show experimental droplet spectra produced using aMalvern Mastersizer X manufactured by Malvern Instruments of Malvern,UK. FIG. 9a shows a typical droplet spectrum produced using a device ofthe type shown in FIG. 1. As can be seen from FIG. 9a, the mediumparticle or droplet diameter is around 10 μm which is at the lower endof desirable droplet diameters for nasal delivery. FIGS. 9b to 9 d showthe equivalent droplet spectra produced by three commercially availablenasal inhalers with FIG. 9b showing the droplet spectra produced by an“Otravine” (Registered Trade Mark) nasal inhaler which comprises asqueezable plastic bottle supplying xylometazoline hydrochloride as anasal decongestant and is supplied by Novartis Consumer Health ofHorsham RH12 4AB, UK, FIG. 9c showing the droplet spectra for a“Flixonase” nasal inhaler and which uses a metering valve and apressurised reservoir and which supplies fluticasone propionate and issupplied by Allen & Hanburys of Stockley Park, Middlesex UB11 1BT, UKand FIG. 9d showing the droplet spectrum output by a “Beconase” pumpaction nasal inhaler which comprises beclomethasone dipropionate and isalso supplied by Allen & Hanburys. As can be seen from a comparison ofFIGS. 9b to 9 d with FIG. 9a, the three conventional inhalers produce alarger range of particle or droplet diameters and control over thedroplet sizes is poor in comparison to that achievable with theelectrohydrodynamic device shown in FIG. 9a. It should also be notedthat the conventional inhalers do not charge the droplets and rely onturbulence and inertia alone to deposit the droplets. Furthermore, theperformance of conventional propellant inhalers is very dependent on theair flow in the nasal passages that can be generated by the user.

The operation of the inhaler 1 shown in FIG. 1 has been tested on modelsof the nose and it has been found that the resulting charge spraysdeposit evenly over the conductive surface representing the interior ofthe nose. The liquid used in these experiments had an electricalresistivity of 4500 Ωcm, a surface tension of 30 mN/m (milli Newtons permetre) and a viscosity of 2.4 cP (centipoise) and a voltage in the rangeof 8 to 12 kV was applied between the first and second electrodes.

The embodiments described above are intended primarily for comminutingliquids of relatively high resistivity such as oils and alcohol. FIG. 10shows a modified version of the inhaler shown in FIG. 2 that is suitablefor comminuting very electrically conductive liquids such as water andsalt solutions.

In the inhaler 300 shown in FIG. 10, the air path tube 33 shown in FIG.2 is replaced by an air path tube 330 in the form of a hollow bodydefining an air channel 330 a which extends through an aperture 32 inthe wall 3 a to terminate in a ring-like nozzle outlet 331 surroundingthe outlet nozzle 10 a. In all other respects, the inhaler 300 shown inFIG. 10 is the same as that shown in FIG. 2.

The inhaler 300 operates in the same way as the inhaler 3 shown in FIG.2 apart from one significant aspect. Thus, when a user takes a sharpintake of breath through a nostril using the inhaler 300, a fast movingstream of air is supplied via the nozzle 331 to the area in whichcomminution occurs. The air flow from the nozzle 331 acts to sheardroplets that are electrohydrodynamically formed from liquid issuingfrom the outlet nozzle 10 a so resulting in droplets that are smallerthan they would be without the air flow. This enables the inhaler to beused for conductive liquids such as water and salt solutions which areotherwise difficult to comminute electrohydrodynamically.

Experiments have been carried out using tap water as the liquid to becomminuted with a liquid supply pipe having an outlet nozzle 10 a withan internal diameter of 0.2 mm and with 2.5 kilovolts applied betweenthe first and second electrodes 11 and 12. The diameter of the tube isselected in accordance with the average expected nasal inhalation rateof a user to provide an air flow rate from the nozzle 331 sufficient tocause shearing, in this example 10 m/second. Where the air flows atapproximately 20 to 30 litres/minute through a tube which is coaxialwith and surrounding the outlet nozzle, then generally the tube outletshould have an area of a few square millimetres so as to be comparablewith the air flow impedance provided by the nasal passages.

Droplets having a diameter of approximately 20 micrometers weredetected. The droplet charge to mass ratio was determined to beapproximately 10⁻⁴ coulombs/kilogram. The droplets were thussignificantly smaller than they would have been without the air flow.

The air flow rate of approximately 10 m/second mentioned above issufficient to cause shearing and is roughly equivalent to the air flowgenerated by a relatively healthy person taking a sharp intake ofbreath.

It will be appreciated that the modification described with reference toFIG. 10 may be used in combination with any appropriate ones of themodifications described with reference to any one of FIGS. 4 to 8 aboveso that, for example, the counter electrode 12 may be positioneddownstream of the first electrode 11 as shown in FIG. 5. It will also beappreciated that one, two or more air flow nozzles may be provided inthe vicinity of the comminution area or site. All that matters is that asufficient air flow is achieved at the comminution area or site to causeshearing without causing undue turbulence. In this regard, it will benoted that as shown in FIG. 10, the outlet nozzle 331 is directed so asto provide an air flow extending obliquely of the direction in whichliquid issues from the outlet nozzle 10 a.

Apart from the reasons given in the introduction of this application, aperson skilled in the art may have thought that it would be undesirablefor the user of an inhaler to inhale charged droplets because the supplyof charge to the user would, if the user was not earthed during use ofthe inhaler, result in a voltage rise of the user which could result inthe user experiencing an unpleasant electrical shock when hesubsequently was connected to earth.

The present inventors have, however, found that the rise in the voltageof an unearthed user during a single use of an inhaler embodying theinvention is not sufficiently large to result in an unpleasantelectrical discharge. Also, the amount of charge transferred to the usermay, if desired, be controlled to a minimum. This may be achieved by,for example, formulating the liquid carrying the medicament beinginhaled with a higher concentration of the active ingredient ormedicament in the liquid than is normal with aqueous solutions. Thus asmaller amount of liquid need be inhaled to deliver the required dose.This reduces the overall space charge and facilitates entrainment of thecomminuted matter in the air flow through the inhaler. Typically, theconcentration may be increased by five fold (say from 10% to 50% byvolume of the active ingredient).

If prolonged or continuous treatment is required, then the inhalersdescribed above may be modified to periodically reverse the polarity ofthe voltage supplied by the high voltage generator so that the userreceives droplets of one polarity charge followed by droplets of theopposite polarity charge, thereby inhibiting any significant rise in thevoltage of the user. One simple way in which this may be achieved is touse as the high voltage source a piezoelectric generator which ismanually activated by the user using a cam and lever arrangement becausethis automatically provides a polarity reversal with the voltagegenerated when the crystal is squeezed being of opposite polarity to thevoltage generated when the crystal is released.

In each of the examples described above, the high voltage is applied tothe second or counter electrode. However, the second electrode could beomitted and the first electrode charged directly to the required highvoltage, especially if a low power, low capacitance, high voltagegenerator, such as a piezoelectric generator, is used.

FIG. 11 shows a diagrammatic part-cross-sectional view similar to FIG. 2of another embodiment of an inhaler in accordance with the presentinvention where the first electrode is directly charged.

The inhaler 301 shown in FIG. 11 has two liquid supply pipes 10 eachhaving an outlet nozzle 10 a. The pipe 10 is coupled to a correspondingpump 9 so as to receive liquid from a corresponding reservoir 8.Although not shown explicitly in FIG. 11, each pump 9 is coupled betweenthe delay circuit 120 and the negative terminal of the voltage source 5.Each of the liquid supply pipes 10 has supported within it a firstelectrode 11 in the form of a conductive core. The first electrode 11 ofone liquid supply pipe 10 is coupled to the high voltage output of thehigh voltage generator 7 (not shown in FIG. 6). A further high voltagegenerator 7′ providing a high voltage of the opposite polarity, negativein this case, has its high voltage output coupled to the first electrode11 of the other liquid supply pipe 10. In this case, either the liquidshould be sufficiently highly resistive to inhibit the direct chargingof the first electrodes 11 causing a voltage rise at the pump or thepump should be electrically isolated from the liquid.

The air flow path shown in FIG. 11 is also different from that shown inFIG. 2. Thus, in the inhaler 301 shown in FIG. 11, the insulativetubular body 33 of FIG. 2 is replaced by an insulative tubular body 333which passes through the aperture 32 in the wall 3 a so as to terminateat an air outlet nozzle 334 which, as shown in FIG. 11, is coaxial withand symmetrically disposed between the two liquid outlet nozzles 10 a.The inhaler 301 shown in FIG. 11 operates in a similar manner to theinhaler shown in FIG. 2 with the exception that two opposite polaritysprays or comminutions are produced. The air flow from the air outletnozzle 334 is sufficient to keep the two opposite polarity comminutionsapart so that two opposite polarity comminutions are supplied to thenozzle passages. This has the advantage of enabling charged, comminutedmatter to be supplied to the nasal passages without altering the overallcharge of the body of the user. Typically, the longitudinal axes of thetwo liquid supply pipes may be 12 to 15 mm apart.

It should be appreciated that the modifications described with referenceto FIG. 11 may be used in combination with the modifications describedwith reference to any one of FIGS. 4 to 8 above.

In each of the embodiments described above the air flow rate iscontrolled either by how hard the user sniffs or by, in the case of FIG.8, the operation of the pump 102. Further control of the air flow ratein any of the above described embodiments may be provided by means of avalve in the air flow path. As an example, FIG. 12 shows part of theinhaler shown in FIG. 2 with a flap valve or choke 301 pivotally mountedin the air flow path 33. The flap valve may be operable by means of anyconventional mechanism, for example, the flap valve may be manuallyrotatable by a user rotating a knob mounted to the outside of thehousing or pivoting movement of the flap valve may be controlledmechanically using a camming arrangement or electromechanically using acamming arrangement and a solenoid, for example, or may be arranged tobe present by a doctor, for example. Other conventional forms of valvesmay also be used.

As described above, the air flow from the outlet nozzle 334 serves tokeep the opposite polarity sprays or comminutions apart. The amount bywhich the opposite polarity comminutions are kept apart, and so a degreeof mixing can be controlled by controlling the air flow rate through thepipe 334 by, for example, providing a throttle or like valve in the airflow pipe 334. This air flow valve may be preset by the doctor or atfactory level (for example in dependence upon the active ingredient tobe delivered by the inhaler), or may be settable by the user. The zoneof deposition of the comminuted matter in the nasal passages can becontrolled by controlling the overall charge of the comminuted mattersupplied to the nostrils of the user so enabling the area to which theactive ingredient is to be delivered to be targeted by adjusting the airflow rate with an air flow control valve.

It will be appreciated that different users or different patients mayhave different nasal inhalation rates which, with conventionalpropellant nasal inhalers, would cause the inhaled material to bedeposited more deeply into the nasal passages than if the inhaler wasbeing used by a person with a lower nasal inhalation rate. However, thenasal inhaler shown in FIG. 11 has the advantage that a person with arapid nasal inhalation rate will cause a more rapid flow of air from theair outlet nozzle 334 than will a person with a low nasal inhalationrate so that the person with the high nasal inhalation rate will receivemore highly charged, less mixed, comminuted matter than the person withthe low nasal inhalation rate. As more highly charged matter tends topenetrate less deeply into the nasal passages, the inhaler shown in FIG.11 provides a self-adjusting effect because the tendency of a greaterinhalation rate to cause material to be deposited more deeply into thenasal passages is counteracted by the greater charge tending to causethe material to be deposited less deeply into the nasal passages.

In the arrangement shown in FIG. 11, the liquid outlets 10 a areparallel to one another. However, the liquid outlets may be angledtowards one another, for example at 45° to the longitudinal axis L ofthe inhaler, which may increase the degree of mixing.

The overall charge on the comminuted matter delivered by the inhaler andthus the depth to which that matter penetrates into the nasal passagesmay also be controlled by, in addition to or instead of controlling theair flow rate, controlling the relative voltages applied to the twofirst electrodes by adjusting the voltages supplied by the high voltagegenerators 7 and 7′ and/or by adjusting the relative flow rates ofliquid to the outlet nozzles 10 a. These adjustments may be adjustmentsthat can be made at factory level so that a single inhaler constructioncan be adapted within the factory for delivery of different doses (forexample for children and adults) of the same active ingredient or toenable the same inhaler to be used to deliver different activeingredients which require different dosages. As another possibility, thevoltages supplied by the generators and/or the flow rates may beadjustable by a doctor or nurse under clinical conditions or apharmacist or the patient or user himself where it is acceptable for theuser to control the dose supplied.

As described above, it is assumed that the same liquid is supplied tothe two liquid supply pipes 10. If this is the case and relative flowrate adjustment is not required, then a single reservoir 8 and a singlepump 9 may be provided. Also, instead of providing separate negative andpositive polarity high voltage generators, a single generator providinga high voltage of one polarity to one of the first electrodes 11 may beprovided and the other electrode may be connected to earth (ground) sothat, in practice, it is charged by induction from the directly chargedfirst electrode. This has the advantage of requiring only a single highvoltage generator so reducing the overall costs and reducing the spacerequired within the inhaler to accommodate the high voltage generator.

Where, as shown in FIG. 11, respective reservoirs and pumps 8 and 9 areprovided, then the two liquid supply pipes 10 may be supplied withdifferent liquids that, when the opposite polarity comminutions aregenerated, interact with one another. For example, the two liquids maycontain or comprise respective reactive components that, when the twoopposite polarity comminutions are produced, intermingle and react withone another so as to produce the required active ingredient. Thisenables, for example, short shelf life active ingredients to be formedonly as and when needed. As another possibility, the two liquid supplypaths may provide separate active ingredients for which reaction is notdesirable but which lose their relative efficacy if they are in thepresence of one another for any length of time. As another possibility,one of the liquids may contain a blowing agent which, when comminutedmatter contained in the blowing agent reacts with the opposite polaritycomminuted matter, causes expansion of the droplets or particles of theother comminuted matter to form low density particles, for examplespheres, which can penetrate deeper into the nasal passages. As anotherpossibility, where the liquid issuing from one of the outlets producescomminuted matter in liquid or gel-like form, then, when the twoopposite polarity comminutions mix, the liquid or gel-like comminutedmatter may cover or coat particles of the other comminuted matter toform, for example, microcapsules or coated short fibres or fibrilsenabling slow release of active ingredient from the cores of the coatedparticles. The coating material may contain a bioadhesive to preventmucocillary clearance and to facilitate long term or sustained releaseof the active ingredient when used in conjunction with controlledrelease products.

Another advantage of having two liquid outlets is that the overall rateat which the active ingredient is delivered to the nasal passages shouldbe higher than if only a single liquid outlet nozzle is used. It will beappreciated that more than one pair of liquid outlets may be used andthat it is not necessary for there to be equal numbers of positive andnegative charged first electrodes especially where, if the arrangementallows complete mixing of the comminutions, a residual charge should beensured.

Another advantage of providing plural nozzles to achieve oppositepolarity comminutions is that the comminution sprays will be morestrongly attracted to one another than to the walls of the housing andso the possibility of deposition of comminuted matter onto the walls ofthe housing should be reduced.

Also, the arrangement shown in FIG. 11 should enable larger sizedroplets or particles of comminuted matter to be produced carrying agiven charge.

It will be appreciated that, although the counter electrodes 12 are notnecessary in the arrangement shown in FIG. 11, the arrangement shown inFIG. 11 could be adapted to provide counter electrodes in a similarmanner to that described above with reference to FIG. 2 with therespective counter electrodes being coupled to the respective negativeand high voltage generators 7 and 7′ and the first electrodes 10 beingcoupled to the negative terminal of the voltage source or to the highvoltage generator of opposite polarity It should also be appreciatedthat the counter electrodes need not be coated with a dielectricalthough this is often preferable. This arrangement may facilitate useof the inhaler shown in FIG. 11 with more conductive liquids.

In the arrangement shown in FIG. 11, the air supply outlet 334 isdisposed centrally of the two liquid outlets. Although this ispreferable where it is desired to keep the two opposite polaritycomminutions apart, where at least some mixing is desired, then the airoutlet may surround the liquid outlets and, for example, air inletapertures may be provided in the housing wall 4 a. Providing the airoutlets around the liquid outlets should, in addition to facilitatingdesired mixing, provide an air curtain to inhibit or at least reducefurther the possibility of deposition on the walls of the housing.

As discussed in WO98/03267, in electrohydrodynamic comminution, theintense electric field to which liquids issuing from the nozzle outlet10 a is subject establishes a standing wave along the surface of theliquid producing at least one cusp or cone (depending upon the size ofthe outlet 10 a) which emits a jet or jets of charged liquid. Smallperturbations inevitably occur in the liquid jet resulting in a growthwave which causes the jet to become unstable and the net electricalcharge in the liquid provides a repulsive force which counteracts thesurface tension forces in the liquid to cause comminution. The growthwave will have a natural frequency and it has been found that the pointat which initiation of the growth wave occurs in the jet can becontrolled by superimposing upon the applied high voltage an AC signaldifferent from the natural frequency of the growth wave enabling thesize of the resulting droplets to be controlled.

The present inventors have found that, instead of a monodispersedcomminution, a comminution having droplets of two or more well-definedcontrolled diameters can be produced by superimposing on the highvoltage signal an oscillating signal comprising one or more superimposedfrequencies close to natural frequency of the growth wave for the liquidbeing comminuted.

As shown schematically in FIG. 13, a pulse or signal generator 70 iscoupled to the high voltage supply line 7 a of the high voltagegenerator by means of a high voltage capacitor C. However, it might bepossible to use the natural frequency of the high voltage generator 7and to retain some AC ripple on the H.V. output line 7 a.

Any suitable form of pulse or signal generator which may be powered bythe voltage source 5 (see FIG. 2 for example) of the inhaler may beused. For example, the pulse/signal generator 70 may comprise a numberof voltage controlled oscillators each of which receives a respectivedifferent drive voltage derived in known manner using voltage dividingor multiplying techniques from the voltage source. As anotherpossibility, a numerically controlled oscillator may be used. Forexample, the pulse/signal generator may comprise a digital memorystoring at sequential addresses numerical values which are read out insequence from the memory and supplied to a digital-to-analogue converterto reconstitute the desired wave shape. In such a case, a signalrepresenting the superimposition of two or more frequencies may bedirectly generated from the numbers stored in the memory. Reference maybe made to standard electronics textbooks such as ‘The Art ofElectronics’ by Paul Horowitz and Winfield Hill for details ofoscillators which may be used to provide the pulse/signal generator 70.

FIG. 14 illustrates how a superimposed varying amplitude voltage canaffect droplet formation with large and small amplitude impulses or“kicks” (illustrated schematically by line 71) applied to the H.V.output line giving rise to two different size droplets d and D.

When the inhaler shown in FIG. 2 is modified in this manner, in use,liquid issuing from the outlet nozzle 10 a is electrohydrodynamicallycomminuted and is deposited on the conductive surface inside the nostrilas the user inhales as described above. However, the smaller dropletswhich carry less charge and have lower inertia will travel further intothe nasal passages than the larger droplets so enabling a more uniformdeposition along the length of the nasal passages of the medicamentbeing delivered.

It will be appreciated that superimposing three or more frequencies willallow three or more different size droplets to be produced in acontrolled manner.

Instead of superimposing the different frequencies, different frequencysignals may be supplied in sequence to the high voltage line 7 a so thatthe size of the droplets produced changes in a controlled manner withtime depending upon the particular drive frequency applied at the timethe droplets are generated.

The arrangement discussed above with reference to FIGS. 13 and 14assumes that the drive signals are sine waves. However, this need notnecessarily be the case and, for example, short duration spikes having apulse width of 1 microsecond or less may be used. Typically the drivesignals provided by the pulse generator 70 will have an amplitude ofabout 2% of the high voltage, for example 10-100 volts and a frequencyin the range of 50 kHz to 10-50 MHz, depending upon the desired size ofthe droplets.

Another possible form of oscillation device is a piezoelectric resonatorwith two or more resonators arranged to resonate at differentfrequencies being provided to achieve the required drive frequencies.

FIGS. 15 and 16 show schematically parts of further modified versions ofthe inhaler shown in FIG. 2.

In the arrangement shown in FIG. 15, the pump 9 is arranged to supplyliquid to three liquid supply pipes 101, 102 and 103 each having acorresponding outlet 101 a, 102 a and 103 a and each containing aconductive core or rod 111, 112 and 113. The conductive core or rod ineach case is coupled to the earth terminal of the voltage generator 5via line 5 a while a second electrode 121, 122 and 123 carried by theinsulative supply pipe 101, 102 and 103 is coupled to the high voltageoutput line 7 a from the high voltage generator. Each of the supplypipes 101 to 103 has a flow regulating valve V1, V2 and V3. Each flowregulating valve V1, V2 and V3 controls the rate of flow of liquidthrough its associated liquid supply pipe so that the rate of flow ofliquid from each of the outlets 101 a, 102 a and 103 a is different. Anysuitable form of valve, for example a simple mechanical throttle valveor an electromechanical solenoid valve, may be used. Because the flowrates to the respective outlets 101 a, 102 a and 103 a are different,the size of the droplets produced during electrohydrodynamic comminutionfrom the respective outlets will be different. Accordingly, theembodiment shown in FIG. 15 enables three different sizes of droplets tobe produced by providing respective different flow rates for the threeliquid supply pipes.

It will be appreciated that two, three or more liquid supply pipeshaving different liquid flow rates may be used and that the liquid flowrates may be prefixed or may be adjustable by the user. The embodimentshown in FIG. 15 enables simultaneous production of different sizedroplets. Sequential production of different size droplets may beachieved by having a single liquid supply pipe and adjusting the flowrate with time by controlling the degree to which the liquid supplyvalve is open.

FIG. 16 illustrates another modification. In this case, the pump 9 isprovided with two or more liquid supply pipes 104 and 105 each having acentral conductor or rod 114 and 115 providing a first electrode. Inthis case the second electrode 124 is mounted to the housing 4 wall. Inthis case, the liquid supply pipes 104 and 105 are of differentcross-sections and therefore provide different liquid flow rates.

As another alternative, different pumps providing different flow ratesmay be used for the different liquid supply pipes.

The generation of comminutions at the different outlets in FIGS. 15 and16 may be synchronised by superimposing upon the high voltage signal online 7 a a drive signal comparable to the natural frequency of thegrowth rate using the pulse generator 70.

In each of the embodiments described above, an air flow is generatedwithin the lower portion 4 a of the housing. In order to avoid airmovements disrupting the Taylor cone required at the liquid outlets forelectrohydrodynamic comminution, an annular shield may be providedaround the liquid pipes in the immediate vicinity of the liquid outlets10 a.

In each of the embodiments described above, the inhaler is designed toenable multiple doses to be supplied from a single reservoir orreservoirs 8. The inhaler 1 may, however, be a single dose inhaler witha reservoir containing only sufficient liquid formulation to provide asingle dose. Where this is the case, then the counter 6 and LED 13described above with reference to FIG. 3 may be omitted. In the case ofa single dose inhaler, the liquid supply components may be provided as areplaceable plug-in cartridge that can be replaced by the user. Wherethis is the case, then for ease of manufacture and because thesecomponents are relatively cheap, the liquid cartridge will generallyinclude the first electrodes 11, and the electrodes 12 if present and ifnot carried by the housing portion 4 a. As another possibility, theinhaler may be provided with a carousel or magazine of capsules whichcarousel or magazine is capable of indexed movement so that, after eachuse of the inhaler, a fresh capsule is moved into place for the nextuse. Such a magazine may be in the form of a strip carrying the capsuleswhich is, for example, wound from one spool to another as the capsulesare used up.

In the embodiments described above, the inhaler has a single outlet fora single nostril. The inhaler may be provided with twin outlets, one foreach nostril.

Although particular forms of electrohydrodynamic comminution means havebeen described in the examples given above, it will be appreciated thatother forms of electrohydrodynamic comminution means can be used. Also,other forms of electrically operable pump may be used.

Electrically or electromechanically operated valves may be provided atappropriate points in the liquid flow path from the reservoir to theoutlet 10 a so as to inhibit leakage and maintain microbial integrity.

Although the above arrangements are described with reference to thesupply of an active ingredient to a human being (solely by the user orwith the assistance of a doctor, nurse or carer), it will, of course, beappreciated that the device may be adapted for use with other mammalswith the air flow activation being controlled as described withreference to FIG. 8 by a veterinarian or other person.

The active ingredient to be supplied by the inhaler may be any agent orsubstance to provide a desired effect in the user. For example, theactive ingredient may be a medicament for use in the treatment by way oftherapy, surgery or diagnosis of an animal body such as a human being orotherwise to improve quality of life. For example, the medicament may benicotine, morphine, a vitamin, an antiseptic, an anti-inflammatory,antibiotic, anti-cancer agent or other pharmaceutical product, avaccine, a protein, an enzyme, DNA or DNA fragments and so on becauseelectrohydrodynamic comminution enables delivery of large moleculeswithout denaturing them.

The liquid formulation within which the active ingredient is suppliedmay be a solution, emulsion, suspension or microsuspension or any othersuitable liquid form. Because viscous liquids (including oils) such asglycerine and linoleic acid can be comminuted using electrohydrodynamiccomminution, the carrier liquid can be optimised for the activeingredient so that, for example, where the active ingredient is alipophilic compound as may be the case for a drug or medicament, thenthe use of electrohydrodynamic comminution should simplify thepreparation of the formulation for that active ingredient. Also, the useof oils and emollients has the advantages that oil-based medicamentspermeate cell membranes better allowing more rapid absorption of themedicament when inhaled into the nasal passages. Also, oils andoil-based formulations should cause less irritation to the nasalpassages than alcohol formulations or aqueous salts. Also oils and otherlow conductivity liquids produce droplets with a low charge to massratio so that the charge spray expands at a lower rate, reducing thelikelihood of internal deposition within the device. Furthermore, suchlow conductivity liquids are also less likely, because they are morehighly resistive, to initiate short circuits.

As is known in the art, it is extremely difficult to comminute highlyelectrically conductive liquids satisfactorily using electrohydrodynamiccomminution without the use of surfactants which may irritate the nasalpassages and so are undesirable for nasal inhalation. The use ofrelatively highly conductive liquid formulations may, however, beunavoidable. For example, it may be that the amount or type of activeingredient required renders the liquid formulation highly conductiveand/or the carrier liquid required, for example water or a water/ethanolmixture containing ionic components, renders the liquid highlyconductive. The present inventors have, surprisingly, found that it ispossible to obtain satisfactory electrohydrodynamic comminution of suchrelatively highly conductive liquids without the use of surfactants byincorporating an additional component into the liquid formulation in theform of a medium to high molecular weight polymer. This polymer may be asynthetic or naturally occurring polymer and the molecular weight may,typically, be in the range 40,000 to 400,000.

Experiments have been carried out using a liquid formulation consistingof 70% ethanol and 30% 0.5 mol water Nacl solution (salt water) to mimica liquid formulation carrying an active ingredient.

A first set of experiments was carried out using PVA (polyvinyl alcohol)as the polymer. For this polymer, a molecular weight of 125,000 waschosen for the experiment. Details of these experiments are set out intable 1 below. The maximum stable flow rate was 3 microlitres/second(ml/s) per nozzle.

TABLE 1 Resistivity/ Viscosity/ Example Formulation Ωm cP 1 0.1 g PVA in5.54 10 10 ml liquid formulation 2 0.2 g PVA in 4.20 24 10 ml liquidformulation 3 0.3 g PVA in 4.80 72 10 ml liquid formulation 4 0.4 g PVAin 5.21 110 10 ml liquid formulation 5 0.5 g PVA in 5.10 200 10 mlliquid formulation 6 0.6 g PVA in 5.21 360 10 ml liquid formulation 70.7 g PVA in 5.25 700 10 ml liquid formulation

In each of examples 1 to 7 satisfactory electrohydrodynamic comminutionwas achieved. Microscope photographs of the resultant comminutions weretaken and it was found that, surprisingly, the geometry or structure ofthe comminuted matter varied with the amount of polymer added to theformulation. Thus, when the amount of polymer was 0.1 g in 10 ml, theresulting comminuted matter was granular in appearance consisting ofspheroidal or near-spheroidal particles. When the amount of PVA wasincreased to 0.2 g, then the comminuted matter was still granular butsome of the granules had tails or were attached to fibrils. As theamount of PVA was increased, that is going from example 2 to example 7,the amount of fibril or tail formation increased so that at example 7the majority of the comminuted matter was formed of small fibres orfibrils.

Similar experiments were also carried out using PVP (polyvinylpyrrolidone). Table 2 shows the results of experiments carried out usinga PVP molecular weight of 360,000 and a maximum flow rate of 1.5microlitres/second per nozzle.

TABLE 2 Viscosity/ Example Resistivity/Ωm cP Product 8 0.2 g PVA in 4.7410 10 ml liquid formulation 9 0.4 g PVA in 4.76 60 10 ml liquidformulation 10 0.6 g PVA in 5.36 180 10 ml liquid formulation 11 0.8 gPVA in 5.20 260 10 ml liquid formulation 12 1.0 g PVA in 5.32 480 10 mlliquid formulation 13 1.2 g PVA in 5.82 740 10 ml liquid formulation

Again, in each of examples 8 to 12, satisfactory electrohydrodynamiccomminution was achieved. Again, microscope photographs were taken andagain the geometry or structure of the comminuted matter was found tochange with the amount of polymer added to the liquid formulation. Thus,where the amount of polymer was 0.2 g in 10 ml (millilitres), thecomminuted matter was generally granular with few fibrils or tails, with0.4 g PVP in 10 ml of the liquid formulation more fibrils or tails wereseen, while with 0.6 g PVP in 10 ml of the formulation significantnumbers of tails and fibrils were seen with few granular components.Thereafter, the number of fibrils and short fibres seen increased. As aresult of further experiments carried out, a formulation with 0.5 g ofPVP in 10 ml of the liquid formulation was found to produce granularmaterial with a good proportion of tails or fibrils.

It can thus be seen that, surprisingly, controlling the amount of mediumto high weight polymer added to the liquid formulation enables thegeometry or shape of the comminuted material to be controlled so thatthe comminuted material can be varied from granular particles to shortfibres and fibrils with, in between, the comminuted material consistingof granular matter some of which has short tails or attached fibrils.The ability to control the shape or geometry of the comminuted matter isadvantageous because this means that the shape of the comminuted mattercan be tailored to the desired usage. Generally, the fibrils or tailswere found to be semi-solid and capable of adhering better to surfacessuch as the surfaces of the nasal passages and/or to themselves, soreducing the possibility of mucocillary clearance. Also, being able tocontrol the size of the comminuted matter from very small granularparticles having dimensions less than 1 micrometre to short fibres orfibrils enables the rate at which active ingredient is taken up by themucous membranes to be controlled with very small particles enablingfast uptake and larger particles enabling slower, more sustained releaseof the active ingredient. Thus, by tailoring the geometry of thecomminuted matter, the rate of delivery of the active ingredient can becontrolled.

The use of electrohydrodynamic comminution as described above to enabledelivery of active ingredients by inhalation through the nasal passagesenables the control of the rate and location of uptake of the activeingredient so that, for example, the active ingredient can be deliveredrapidly to the brain with low or little systemic uptake which isparticularly important where the drug to be delivered may havedeleterious systemic side effects.

The above example describes inhalers for supplying an active ingredientvia the nasal passages. However, where the modification shown in FIG. 8is provided so that inhalation by the user is not required, supply of anactive ingredient to other body areas, cavities or organs, or onto orinto a wound is possible. Such a device may be used for supply of activeingredients to the eye because the electrodes are not exposed soinhibiting the possibility of electrical shock. Where the device isadapted for supply of an active ingredient to the surface of the eye,then the outlet of the housing may, for example, be shaped so as toconform to the eye socket. A device having the structure of an inhalerdescribed above with the adaptation shown in FIG. 8 may be used tosupply pre- or post-operative active ingredients, for example, toreduce, especially in the case of the eye, the likelihood of scar tissueforming after surgery; to supply antibiotics, antibacterials,anaesthetics and the like to the surface of the eye or into a bodilyorifice; to supply comminuted matter onto an exposed interior surface ofthe body during surgery for example to supply an adhesive to repair anincision in an arterial wall; or to apply wound dressing or medicamentsonto internal or external bodily wounds.

The final form of the comminuted matter will depend upon the liquidbeing comminuted. Thus, for example, if the liquid is such that itstarts to solidify or gel after comminution then solid or gel-likedroplets will be formed. If the liquid starts to solidify or gel justbefore comminution then generally small fibres or fibrils will beformed. Where the device is not being used for inhalation, then the termcomminution is also intended to cover the case where the supplied liquidsolidifies or gels before the applied electric field can break theliquid apart and so forms a single fibre although, strictly, in thiscircumstance the liquid is not comminuted because it does notnecessarily break up.

Other modifications will be apparent to the person skilled in the art.

What is claimed is:
 1. An inhaler, comprising a housing having an outletand an air inlet, the housing containing: a liquid supply componentcomprising: a chamber providing a reservoir for liquid providing anactive ingredient to be supplied to a user and means for supplyingliquid from the reservoir to a liquid outlet (liquid supplying means);and means for creating an electric field (electric field creating means)for causing comminution of liquid issuing from the liquid supplyingmeans outlet in response to air flowing through the air inlet so as toproduce a stream of electrically charged comminuted matter for supply tothe nasal passages via the housing outlet.
 2. An inhaler according toclaim 1, wherein the liquid supplying means has first and secondoutlets; and the electric field creating means comprises a firstelectrohydrodynamic comminution means for subjecting liquid issuing fromthe first outlet to an electrical potential to cause liquid to becomminuted to form a comminution of one polarity; and a secondelectrohydrodynamic comminution means for subjecting liquid issuing fromthe second outlet to an electrical potential to cause the liquid to becomminuted to form a comminution of the opposite polarity, means beingprovided for providing an air flow to the outlet to modify any mixing ofthe two opposite polarity comminutions.
 3. An inhaler according to claim1, wherein the electric field creating means comprises first and secondspaced apart electrodes with the first electrode being provided at oradjacent the outlet of the liquid supplying means; and voltage supplyingmeans operable in response to air flowing through the air inlet toprovide a potential difference between the first and second electrodes.4. An inhaler according to claim 3, wherein the voltage supplying meanscomprises an air flow activated switch for coupling a voltage generatingmeans across the first and second electrodes.
 5. An inhaler according toclaim 3, wherein the air flow activated switch comprises a closuremember and spring biassing means normally biassing the closure memberinto a position closing off the supply of air into the housing throughthe air inlet, the closure member being movable against the springbiassing to a position allowing air to flow into the housing through theair inlet in response to the air flow.
 6. An inhaler according to claim1, wherein the housing is arranged to enable a user to create the airflow by breathing in through the housing outlet.
 7. An inhaler accordingto claim 1, further comprising a pump for creating the air flow.
 8. Aninhaler according to claim 1, wherein the electric field creating meanscomprises: first and second spaced apart electrodes with the firstelectrode being provided at or adjacent the outlet of the liquidsupplying means; and user-operable voltage supplying means for providinga potential difference between the first and second electrodes to createthe electric field for causing comminution of liquid issuing from theliquid supplying means outlet to produce a stream of electricallycharged comminuted matter, the first and second electrodes being spacedfrom the housing outlet and being arranged so as to provide, when apotential difference is applied across them by the voltage supplyingmeans, and electric field which reduces rapidly in the direction ofliquid flow from the liquid supplying means and the housing having anair flow path to the housing outlet for causing liquid comminuted by theelectric field to be entrained by the air flow for supply via thehousing outlet to the nasal passages of a user.
 9. An inhaler accordingto claim 3, wherein the first and second spaced apart electrodes arespaced apart in a direction perpendicular to a flow of liquid from theliquid supplying means.
 10. An inhaler according to claim 3, wherein thesecond electrode is located downstream of the liquid outlet.
 11. Aninhaler according to claim 1, wherein the electric field creating meanscomprises: first and second spaced apart electrodes with the firstelectrode being provided at or adjacent the outlet of the liquidsupplying means; and user-operable voltage supplying means for providinga potential difference between the first and second electrodes to createthe electric field for causing comminution of liquid issuing from theliquid supplying means outlet to produce a stream of electricallycharged comminuted matter for supply via the housing outlet to the nasalpassages of a user, wherein current-limiting means are provided forlimiting the supply of current by the voltage supplying means.
 12. Aninhaler according to claim 11, wherein current-limiting means is coupledto one of the first and second electrodes.
 13. An inhaler according toclaim 11, wherein the current-limiting means comprises a dielectric orsemi-insulating coating or sleeve provided on said one of the first andsecond electrodes.
 14. An inhaler according to claim 8, wherein thevoltage supplying means comprises an air flow activated switch forcoupling a voltage generating means across the first and second spacedapart electrodes.
 15. An inhaler according to claim 14, wherein the airflow activated switch comprises a closure member and spring biassingmeans normally biassing the closure member into a position closing offthe supply of air into the housing through the air inlet, the closuremember being movable against the spring biassing to a position allowingair to flow into the housing through the air inlet in response to a userbreathing in through the housing outlet or in response to an air supplyto the air inlet.
 16. An inhaler according to claim 3, wherein thevoltage supplying means comprises a further electrode positionedadjacent the second electrode and resistive means coupling the secondelectrode to earth, the voltage supplying means being arranged to causethe further electrode to generate an ion current for charging the secondelectrode to an electrical potential sufficient to provide theelectrical potential for causing comminution of liquid issuing from theoutlet.
 17. An inhaler according to claim 1, further comprising: meansfor providing a flow of air towards the housing outlet so as to supplythe stream of electrically charged comminuted matter to the nasalpassages of a user via the housing outlet.
 18. An inhaler according toclaim 1, further comprising: means for shearing comminuted matter(shearing means) issuing from the liquid outlet to produce a stream ofelectrically charged comminuted matter of smaller size than thatproduced by the electric field for supply to the nasal passages of auser via the housing outlet.
 19. An inhaler according to claim 18,wherein the shearing means comprises means for producing airflow in thevicinity of liquid issuing form the liquid outlet.
 20. An inhaleraccording to claim 1, wherein the liquid supplying means comprises meansfor supplying liquid to first and second outlets; and the electric fieldcreating means has a first electrohydrodynamic comminution means forsubjecting liquid issuing from the first outlet to an electricalpotential to cause the liquid to be comminuted to form a comminution ofone polarity; a second electrohydrodynamic comminution means forsubjecting liquid issuing from the second outlet to an electricalpotential to cause the liquid to be comminuted to form a comminution ofthe opposite polarity; and means for providing an air flow to the outletto modify any mixing of the two opposite polarity comminutions.
 21. Aninhaler according to claim 2, wherein the air flow providing means isoperable to keep the two opposite polarity comminutions apart.
 22. Aninhaler according to claim 2, further comprising means for controllingat least one of: 1) the relative flow rates of liquid to the first andsecond liquid outlets; 2) the relative electrical potentials to whichliquid issuing from the first and second outlets is subjected; and 3)the air flow provided by the air flow providing means.
 23. An inhaleraccording to claim 2, comprising a respective reservoir for each liquidoutlet, the reservoirs containing different liquids.
 24. An inhaleraccording to claim 2, wherein the first and second liquid outlets areangled towards one another.
 25. An inhaler according to claim 1, furthercomprising air flow control valve means for controlling the air flowing.26. An inhaler according to claim 1, further comprising: means forcontrolling the size of the components of the comminuted matter.
 27. Aninhaler according to claim 1, further comprising: means for controllingthe size of the comminuted matter such that the communited matter has atleast two different controlled sizes.
 28. An inhaler according to claim1, further comprising means for controlling the diameter of the dropletsso that the comminuted matter consists of droplets each having one of atleast two different controlled diameters.
 29. An inhaler according toclaim 22, wherein the controlling means comprises means forsuperimposing on the voltage supplied by the voltage supplying means analternating or pulsed signal (superimposing means).
 30. An inhaleraccording to claim 22, wherein the controlling means comprises means forsuperimposing on the voltage supplied by the voltage supplying means asignal having two different frequency components for causing thecomminuted matter to contain two different sizes of components(superimposing means).
 31. An inhaler according to claim 29, wherein thesuperimposing means is arranged to superimpose on the voltage suppliedby said voltage supplying means a signal having three or more differentfrequency components for causing the comminuted matter to contain threeor more different sizes of components.
 32. An inhaler according to claim30, wherein said signal is arranged to consist of said frequencycomponents superimposed simultaneously on said voltage in phase with oneanother.
 33. A device according to claim 30, wherein said signal isarranged such that said different frequency components are superimposedone after another on said voltage.
 34. An inhaler according to claim 25,wherein the means for controlling the size of the components of thecomminution comprises means for regulating the liquid flow and/or theliquid composition.
 35. An inhaler according to claim 25, wherein themeans for controlling the size of the comminution components comprises aplurality of subsidiary liquid outlets which together form the liquidoutlet and respective different cross-section supply pipes for supplyingliquid to each different one of the subsidiary liquid outlets.
 36. Aninhaler according to claim 25, wherein the means for controlling thesize of the comminution components comprises a plurality of subsidiaryliquid outlets which together form the liquid outlet each having arespective valve means for controlling the liquid flow from the outlet.37. An inhaler according to claim 1, having a respective housing outletfor each nostril of a user or patient.
 38. An inhaler according to claim1, wherein the air flow is induced other than by inhalation.
 39. Aninhaler according to claim 1, comprising a biologically acceptablecarrier for the active ingredients selected from: an oil, an alcohol, apolymer or a water-based solvent.
 40. An inhaler according to claim 1,comprising a supply of liquid carrying as an active ingredient at leastone of the following: a decongestant, a lipid, a vitamin, an antiseptic,an anti-inflammatory, an antibiotic, an anti-cancer agent, a vaccine, aprotein, an enzyme, a bioadhesive, DNA or DNA fragments, nicotine andmorphine.
 41. A liquid formulation for use in an inhaler in accordancewith claim 1, comprising a biologically acceptable carrier liquid for anactive ingredient and a polymer.
 42. A liquid formulation according toclaim 41, wherein the polymer is a medium to high molecular weightpolymer.
 43. A liquid formulation according to claim 41, wherein thepolymer is PVA or PVP.
 44. A liquid formulation according to claim 41,wherein the polymer is selected from amongst the following: 0.2 to 0.7grams per 10 centiliters of formulation of PVA; 0.2 grams per 10centiliters of formulation of PVA; from 0.2 to 1.2 grams per 10centiliters of formulation of PVP; or 0.5 grams per 10 centiliters offormulation of PVP.
 45. A liquid formulation according to claim 41,further comprising as an active ingredient at least one of thefollowing: a decongestant, a lipid, a vitamin, an antiseptic, ananti-inflammatory, an antibiotic, an anti-cancer agent, a vaccine, aprotein, an enzyme, a bioadhesive, DNA or DNA fragments, nicotine andmorphine.
 46. A delivery device according to claim 1, but differing inthat the device is arranged to supply the active ingredient to themouth, an eye or a bodily orifice and in that air flow is induced otherthan by inhalation or alternatively by oral inhalation when the deviceis arranged to supply the active ingredient to or via the mouth.
 47. Amethod of supplying an active ingredient to the nasal passages of ahuman or animal which comprises using an inhaler in accordance withclaim
 1. 48. A method of supplying an active ingredient to an eye orbodily orifice other than the mouth or nose which comprises using adelivery device in accordance with claim
 46. 49. An inhaler according toclaim 26, wherein the components include droplets.
 50. A dispensingdevice comprising a housing having an outlet and an air inlet, thehousing containing liquid supplying means comprising: a chamberproviding a reservoir for liquid providing an active ingredient to besupplied to a user and means for supplying liquid from the reservoir toa liquid outlet; and means for creating an electric field for causingcomminution of liquid issuing from the liquid supplying means outlet inresponse to air flowing through the air inlet so as to produce a streamof electrically charged comminuted matter for supply to the housingoutlet, the housing outlet being adapted to supply the comminuted mattercontaining the active ingredient to at least one of the mouth and eyeand a bodily orifice of the user.